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Description of key information

Cadmium hydroxide was shown to have no sensitisation potential in the guinea pig according to the Magnusson-Kligman method, using a maximisation method with Freund's complete adjuvant

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
21 Jan 2021 - 14 Apr 2021
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
17 July 1992 version
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Due to the limitation with metals (e.g. false negative findings in the LLNA with certain metals) as per OECD 429 §5, the recommended in vivo test (LLNA study) is also not applicable for this test item. Therefore, the guinea pig study (using the Magnusson and Kligman method) was selected to provide information about the skin sensitization potential of the test item.
The metals industry has historical data to indicate that metals can induce false positives/negatives in LLNA studies; this is confirmed from experiences in test labs.
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source: sponsor ; lot/batch number of test material: CP5275
- Purity: 98.92% ; Expiry date: 04 June 2021

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room Temperature (15-25°C, ≤70% relative humidity)
- Safety precautions: Enhanced safety precautions (half mask at least with P3 filter cartridge, nitrile gloves, lab coat) were applied considering the supplied safety datasheet to assure personnel health and safety.

OTHER SPECIFICS
- Other relevant information needed for characterising the tested material: White solid (in the powder form)
Species:
guinea pig
Strain:
other: LAL/HA/BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: LAB-ÁLL Bt., Hungary
- Females (if applicable) nulliparous and non-pregnant: yes
- Microbiological status of animals, when known: not specified
- Age at study initiation: young adult
- Weight at study initiation: Target body weight: ≥ 250 g at start. The maximum difference of individual animal weights from the mean of the treatment group will not exceed 20%.
- Housing: animals kept in Macrolon cages size IV with certified laboratory wood bedding in groups of up to 3 animals/cage.
- Diet (ad libitum): ssniff Complete feed for Guinea pigs – maintenance produced by ssniff Spezialdiäten GmbH, D-59494 Soest, Germany
- Water (ad libitum): tap water, routinely analysed and is considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study
- Acclimation period: at least 5 days
- Indication of any skin lesions: The health status of the animals assigned to study will be verified by the clinical Veterinarian.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3°C
- Humidity (%): 30 - 70%
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 a.m. to 6.00 p.m.
- IN-LIFE DATES: From: beginning of experiment ; To: end of experiment (no deaths occurred during the experiment)
Route:
intradermal
Vehicle:
CMC (carboxymethyl cellulose)
Concentration / amount:
The test item was used at 1% (w/v) test item formulated in 1% Methyl Cellulose (1% MC) and 1% (w/v) formulated in FCA:Saline (1:1) for intradermal injections.
Day(s)/duration:
1 day / 24 hours
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
epicutaneous, occlusive
Vehicle:
CMC (carboxymethyl cellulose)
Concentration / amount:
Topical application of 0.5 mL for 48 (± 2) hours exposure at a concentration of 75% (w/v) test item in 1% MC for topical sensitization treatment.
Day(s)/duration:
48 hours
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
CMC (carboxymethyl cellulose)
Concentration / amount:
Concentration of 75% (w/v) test item in 1% MC was administered on the left side of all animals. The right side of the animals was treated with 37.5% (w/v) test item in 1% MC on the right side (50% of the maximum challenge concentration (safeguard dose)). Challenge was performed by dermal application of the test item for 24 (± 2) hours with a fully occlusive foil (Closed Patch Test).
Day(s)/duration:
24 hours
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
10 (in test group)
Details on study design:
RANGE FINDING TEST: The dose levels for the main test are selected based on the results of the Preliminary Tests.
A series of test item concentrations were tested to identify the primary irritation following intradermal injection and topical application: 2.5, 1% (w/v) in 1% methyl cellulose (1% MC) were used for intradermal injection; 75% (w/v) concentration in 1% MC for topical application. Local effects were examined and scored approximately 1, 24, 48 and 72 hours after the treatment (in case of intradermal treatment) or after patch removal (in case of topical application). Skin effects were scored for erythema and oedema, any other observations of changes to the skin was recorded if present.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2
- Exposure period: challenge performed two weeks after the induction exposure
- Test groups: 10 animals
- Control group: 5 animals
- Site: right and left dorsal surface or on the back of the animals (approximately 25 cm2)
- Frequency of applications: three pairs of injections during the induction phase and then topical application for 48 hours.
- Duration: 48hours for the epicutaneous exposure
- Concentrations: the test item was used at 1% (w/v) test item formulated in 1% Methyl Cellulose (1% MC) and 1% (w/v) formulated in FCA:Saline (1:1) for intradermal injections and at a concentration of 75% (w/v) test item in 1% MC for topical sensitisation treatment.

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: two weeks after epidermal induction applicatation
- Exposure period: 24h
- Test groups: the test and control guinea pigs were treated the same way
- Control group: the test and control guinea pigs were treated the same way
- Site: left and right flank
- Concentrations: 50% of the test item in an aqueous solution of 0.5% CMC and 0.1% Tween 80 and vehicle only (right flank)
- Evaluation (hr after challenge): 24 and 48 hours
Challenge controls:
Yes, five control guinea pigs were used and simultaneously exposed to 2 injections of FCA and saline in a 1:1 (v/v) mixture, 2 injections of 1% MC and 2 injections of 1% MC formulated in a 1:1 mixture (v/v) of FCA and saline during the sensitisation phase.
Positive control substance(s):
not required
Positive control results:
Not required
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
None
No. with + reactions:
0
Total no. in group:
0
Clinical observations:
Not performed
Remarks on result:
not measured/tested
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
2 injections of FCA and saline in a 1:1 (v/v) mixture, 2 injections of 1% MC and 2 injections of 1% MC formulated in a 1:1 mixture (v/v) of FCA and saline
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
No erythema, oedema or clinical signs of local effects were noted in the control group.
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
Test item at 1% (w/v) test item formulated in 1% Methyl Cellulose (1% MC) and 1% (w/v) formulated in FCA:Saline (1:1)
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No erythema, oedema was noted in the test item treated group. One animal had slight decreased activity from Day 1 to Day 2, however this effect was not detected in other animals and it was not considered to be an unacceptable effect.
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
1% MC for topical sensitization treatment in 0.5mL
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
After topical induction, no erythema, oedema or clinical signs were noted in the control or test groups.
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0.5 mL at a concentration of 75% (w/v) test item in 1% MC for topical sensitization treatment
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No erythema, oedema or clinical signs were noted in the test group
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
None
No. with + reactions:
0
Total no. in group:
0
Clinical observations:
Not performed
Remarks on result:
not measured/tested
Interpretation of results:
GHS criteria not met
Conclusions:
Based on the above mentioned findings in an adjuvant sensitization test (M&K-test) in guinea pigs, Cadmium Hydroxide does not have to be classified and labelled as a skin sensitizer.
Executive summary:

A skin sensitisation study was performed in the guinea pig according to the Guinea Pig Maximisation Test (also known as Magnusson and Kligman) method to evaluate the sensitisation potential of test item Cadmium hydroxide. Parameters monitored during this study included mortality, body weight measurement and local and clinical observations.


The experiment was conducted in compliance with requirements of the OECD No. 406 (1992); Commission Regulation (EC) No 440/2008 of 30 May 2008, B.6 and EPA OPPTS 870.2600 (2003).


Ten test animals were subjected to sensitisation procedures in a two-stage process, induction phase, consisting in an intradermal treatment (three pairs of injections (0.1 mL/site) with and without Freund's Complete Adjuvant (FCA) formulation) and a topical application (0.5 mL for 48 (± 2) hours exposure) (dermal treatment under an occlusive dressing). The test item was used at 1% (w/v) test item formulated in 1% Methyl Cellulose (1% MC) and 1% (w/v) formulated in FCA:Saline (1:1) for intradermal injections and at a concentration of 75% (w/v) test item in 1% MC for topical sensitisation treatment. Five control guinea pigs were simultaneously exposed to 2 injections of FCA and saline in a 1:1 (v/v) mixture, 2 injections of 1% MC and 2 injections of 1% MC formulated in a 1:1 mixture (v/v) of FCA and saline during the sensitisation phase. Since erythema was observed in the preliminary tests (intradermal induction), application of 0.5 ml of 10% sodium dodecyl sulphate (SDS) is not needed prior to topical induction.


Two weeks after the last induction exposure, a challenge dose at a concentration of 75% (w/v) test item in 1% MC was administered on the left side of all animals. The right side of the animals was treated with 37.5% (w/v) test item in 1% MC on the right side (50% of the maximum challenge concentration (safeguard dose)). Challenge was performed by dermal application of the test item for 24 (± 2) hours with a fully occlusive foil (Closed Patch Test).


Animals were assessed for any notable systemic clinical signs once daily and skin reactions were observed and recorded at the following time-points:



  • Intradermal induction exposure: 24 (±2) hours after treatment.

  • Dermal induction exposure: 1 (±5 minutes), 24 (±2), 48 (±2) and 72 (±2) hours after the patch removal.

  • Challenge exposure: 24 (±2) and 48 (±2) hours after the patch removal.


There was no mortality related to the administration of the test item. There was no effect on body weight in any animals.


In conclusion, under the conditions of the present assay the test item Cadmium hydroxide was shown to have no sensitisation potential and is classified as a non-sensitiser, according to current GHS criteria.


The study result triggers the following classification/labelling:


- GHS (rev. 8) 2019: Not classified

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based upon cadmium hydroxide Cd(OH)2 skin sensitization data and according to Regulation (EC) No 1272/2008, cadmium hydroxide does not require classification as a sensitizer.

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